Abstract 2796: Tumor pharmacokinetics, pharmacodynamics and efficacy analysis of WEE1 inhibitor, zn-c3 in patient-derived xenograft models of glioblastoma

Abstract

Abstract WEE1 kinase regulates G2/M checkpoint transition via phosphorylation of CDK1 and prevents entry into mitosis. WEE1 inhibition increases genomic instability due to G2/M checkpoint inactivation and can result in mitotic catastrophe as monotherapy or when combined with DNA damaging agents. In this study, we evaluated the efficacy as well as pharmacokinetic and pharmacodynamic properties of ZN-c3, a best-in-class WEE1 inhibitor, in orthotopic patient-derived xenograft (PDX) models of GBM. Mice with intracranial tumors were randomized to 80 mg/kg ZN-c3 PO QD x 2 weeks vs. placebo. ZN-c3 levels in plasma and contrast-enhancing tumor tissue were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Unbound fractions were determined by equilibrium dialysis. Immunohistochemistry was performed to assess levels of pCDK1, phospho-Histone H3 (pHH3), and cleaved caspase 3 (CC3). The median unbound concentrations of ZN-c3 were 315 nmol/L and 15 nmol/kg in plasma and tumor tissue, respectively - higher than the biochemical IC50 of ZN-c3 for inhibition of WEE1 (3.8nM). An increase in pHH3(+) cells (0.40% vs. 6.57%, p=0.03) indicated drug-induced mitotic entry upon ZN-c3 treatment. ZN-c3 was potently cytotoxic across multiple patient-derived xenograft (PDX)-derived cell lines (IC50- 150-10000nM). Time and dose-escalation experiments exhibited target engagement at concentrations lower than IC50 values within one hour of treatment. Basal levels of WEE1 and pCDK1 were correlated with cell viability in response to ZN-c3 across multiple PDX cell lines. Overall, ZN-c3 is well tolerated, achieves pharmacologically-relevant unbound concentrations in GBM PDX models, and is associated with significant checkpoint modulation. Preclinical evaluation of ZN-c3 in combination with radiation therapy and DNA damage response pathway inhibitors is currently underway, which will support future combinatorial strategy for glioblastoma treatment. Citation Format: Shwetal Mehta, An-Chi Tien, Sonam Patel, Tigran Margaryan, Anilkumar Thaghalli Shivanna, Leonel Elena, Jennifer Molloy, William Knight, Ruiheng Hon, Mackenna Elliott, Mariya Stavnichuk, Zorana Opachich, Yu-Wei Chang, Chelsea Montgomery, Sarah Himes, Barbara Hopkins, Artak Tovmasyan, Nader Sanai. Tumor pharmacokinetics, pharmacodynamics and efficacy analysis of WEE1 inhibitor, zn-c3 in patient-derived xenograft models of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2796.